Both immunoreactive somatostatin and glucagon are increased in the pancreatic islets of diabetics. The mechanism of this change is uncertain. Since somatostatin lowers the secretion of glucagon, the increase in islet somatostatin could reflect decreased secretion of somatostatin and result in the hyperglucogonemia of diabetes. Alternately, the pancreatic somatostatin increase could be an appropriate although inadequate response to glucagon hypersecretion. The hypothesis to be tested is that somatostatin secretion increases in response to the hypersecretion of glucagon. We propose to investigate the mechanism of increased levels in the pancreatic islets in diabetes utilizing a rabbit model with a spontaneous form of the disease which resembles juvenile diabetes. The technique of affinity chromatography will be utilized to measure somatostatin secretion in the pancreatic venous blood and to separate the two immunoreactive forms of somatostatin found in the pancreas. The roles of glucagon, insulin and growth hormone feedback on somatostatin levels in the pancreatic islet will be investigated. Big somatostatin will be further characterized by the production of antibodies to this peptide. Monolayer culture of the GH1 cell line will be utilized to gain new insights into the mechanism of somatostatin's action, correlating the binding of the tetradecapeptide to the cell membrane with intracellular events coupled to hormonal secretion. Pharmacologic approaches to somatostatin secretion will be applied to the diabetic model with the goal of increasing the endogenous secretion of somatostatin and decreasing glucagon secretion in diabetes.